Pure red cell aplasia and hepatitis in a child receiving isoniazid therapy.

A 7-year-old boy had pure red cell aplasia and clinically significant hepatitis during isoniazid therapy. The former complication had been reported only in adults, and the latter is rare in children.

Decrease in the protein kinase C-catalyzed phosphorylation of an endogenous lung protein (Mr 36,000) following treatment of mice with the tumor-modulatory agent butylated hydroxytoluene.

Butylated hydroxytoluene (BHT) causes transient lung damage in mice, and it can either inhibit or enhance carcinogen induction of tumors in internal organs, such as urethan-induced lung adenomas. Since protein kinase C (Pk-C) may mediate the action of one class of tumor-modulatory agents, the phorbol esters which promote skin tumorigenesis, we are examining the hypothesis that Pk-C is involved in the modulatory effects of BHT on internal organs. Endogenous phosphorylation of a Mr 36,000 cytosolic protein (p36) with a pI of 5.7 was demonstrable in extracts from lung and spleen but not from brain or heart. Phosphorylation required the presence of both Ca2+ and phosphatidylserine, and phosphate was incorporated into seryl and threonyl residues but not into tyrosyl residues. This reaction thus has the characteristics of Pk-C-dependent catalysis. A single i.p. injection of BHT (400 mg/kg body weight) decreased p36 phosphorylation severalfold in both BALB/cByJ and A/J mice. This decrease correlated with the extent of BHT-induced lung damage with regard to both the time course following BHT administration and the dose dependence of BHT. All of the pulmonary effects of BHT are abolished if the mice are pretreated with cedrene, an inducer of drug-detoxifying enzymes. Such treatment with cedrene prevented any BHT-induced decrease in p36 phosphorylation. A decrease in Pk-C specific activity, as measured using histone as an exogenous substrate, which resulted upon BHT treatment may provide a mechanism for decreased p36 phosphorylation. The specificity of this toxicity-related effect of BHT is emphasized by the fact that urethan injection did not detectably affect the phosphorylation of any lung proteins. Both p36 phosphorylation and Pk-C specific activity increased as a function of postnatal age. Thus the extent of p36 phosphorylation was inversely related to the extent of lung cell proliferation in two different physiological states, postnatal growth and regenerative repair following BHT-induced toxic injury. A single BHT injection is sufficient to cause lung toxicity, tumor prophylaxis, or cocarcinogenesis, while tumor promotion requires chronic treatment. P36 phosphorylation also decreased when mice were given multiple BHT injections over a period of 5 weeks. These results are consistent with a hypothesis that decreased Pk-C-dependent phosphorylation of p36 is involved in lung tumor modulation by BHT.

Phosphoproteins in Dictyostelium discoideum.

The phosphoproteins of Dictyostelium discoideum were compared at different stages of development of polyacrylamide gel electrophoresis. Certain phosphoproteins of vegetative amoebae were conserved while others appeared and disappeared during development. Four major phosphoproteins with apparent subunit molecular weights of 50,000, 47,000, 38,000, and 34,000 disappeared precociously in response to exogenous of cAMP. Two membranal phosphoproteins, with apparent subunit molecular weights of 80,000 and 81,000, appeared precociously in response to added cAMP. One of these phosphoproteins, molecular weight 80,000, has been identified tentatively as the "contact site A"glycoprotein. Another membranal protein, with apparent subunit molecular weight of 42,000, unaffected in its appearance by cAMP, has been identified tentatively as phosphoactin.